UC San Diego
Antimicrobial nanoparticle for the treatment of bacterial infection
- Author(s): Pornpattananangkul, Dissaya
- et al.
Liposomes are spherical lipid vesicles with bilayered membrane structure, which have been recognized as one of the most widely used carriers for delivering a myriad of pharmaceuticals. Liposomes can carry both hydrophilic and hydrophobic agents with high efficiency and protect them from undesired effects of external conditions. However, the applications of liposomes are usually limited by their instability during storage. They are inclined to fuse with one another immediately after preparation, resulting in undesired mixing, increase in size, and payload loss. To overcome this limitation, this dissertation will focus on the technology to stabilize liposomes during storage and destabilize at specific conditions in order to allow controllable therapeutic release, as well as demonstrate their application to treat one of the bacterial infection diseases, acne vulgaris. The first area of this research is stimuli-responsive liposomes development, where the liposomes are stabilized by introducing gold nanoparticles to adsorb to their surface. As a result, the liposomes are prevented from fusing with one another and undesirable payload release during storage or physiological environments. Moreover, therapeutic is controllably released depending on environment conditions, such as acidic pH and bacterial virulence factor. In case of acid- responsive liposomes, the bound gold nanoparticles can effectively prevent liposomes from fusing with one another at neutral pH value, while at acidic environment (e.g. pH< 5), the gold particle stabilizers will fall off from the liposomes, thereby reinstalling the fusion activity of liposomes. The fusion activity of the stabilized liposomes is found to be 25% at pH=7, in contrast to 80% at pH=4. Another stimulus that can activate drug release from liposomes is virulence factor released from bacteria themselves, such as bacterial toxin. When nanoparticle- stabilized liposomes encounter with bacteria that secrete toxin, the toxin will insert into the liposome membranes and form pores, through which the encapsulated therapeutic agents are released. The released drugs subsequently impose antimicrobial effects on the toxin-secreting bacteria. It was observed that in the presence of toxin- secreting bacteria, 100% of the encapsulated antibiotics were released from the gold nanoparticle-stabilized liposomes and bacterial growth was effectively inhibited by the released antibiotics in 24 h. The second area is to demonstrate an application of the invented technology to treat acne vulgaris by delivering therapeutics to the acne -causing bacteria, named Propionibacterium acnes (P.acnes). First, lauric acid (LA), an antimicrobial with strong activity against P. acnes, is encapsulated in liposomes (LipoLA), which is shown to effectively kill the bacteria by fusion with the bacterial membrane, resulting in a direct insertion of LA molecules to the membrane and destruction of its surface structure in vitro and in vivo. The system is then further improved by the acid-responsive technology based on the fact that the acne lesions on human skin are typically acidic. Demonstrated by fluorescent and antimicrobial experiments, the bound gold nanoparticles effectively prevent LipoLA from fusing with one another at neutral pH value. However, at acidic condition, the gold particles detach from LipoLA surface, allowing the fusion with P.acnes membrane and lauric acid delivery, resulting in a complete killing effect. The stimuli-responsive liposomes presented here provide a new, safe, and effective approach to treat bacterial infections. They can be broadly applied to treat a variety of infections caused by bacteria that reside in acidic environment and secrete pore-forming toxins